The adult mammalian central nervous system contains a population of immature, undifferentiated, multipotent cells, neural stem cells (NSCs) that may be called upon for repair in neurodegenerative and demyelinating diseases. NSCs may, in turn, give rise to oligodendrocyte progenitor cells (OPCs) and other myelinating cells, as well as neural and glial precursors. The capacity of NSCs to repair damage in the adult has been demonstrated in several experimental systems. However, in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE) remyelination and neuro-regeneration do not occur to a sufficient extent. We will examine the hypothesis that endogenous progenitors may be a target of inflammation in MS and EAE resulting in compromise of the cellular pools that have repair potential. In aim 1, we will examine the effects of acute inflammation on the dynamics and multipotentiality of endogenous neural stem and progenitor cells in vivo. Our hypothesis is that acute inflammation engages the NSCs to initiate their program of proliferation and differentiation. We plan to investigate recruitment, proliferation, differentiation, and apoptosis of endogenous progenitors during the course of EAE in a relapsing-remitting disease model in SJLx PLJ mice and the chronic disease model in C57BL/6 mice. In aim 2, we will investigate the triggers for NSC activation and proliferation during EAE and how do they affect the regenerative capacity of stem cells. Our hypothesis is that some immune mediators are beneficial while others may be detrimental in the repair process. We will dissect the effects of specific inflammatory mediators on NSC function (proliferation, self renewal, and differentiation) by manipulating the levels of these mediators in vitro and by using cells from specific cytokine KO mice to study these effects in vivo. In aim 3, we will investigate the effects of chronic inflammation on the intrinsic repair capacity of stem/progenitor cells. We will isolate progenitor cells from the spinal cord and SVZ in animals with chronic disease and examine in vitro their differentiation and self-renewing capacity. We will then examine the impact of chronic inflammation on the molecular program of neural stem/progenitors cells by microarrays. These investigations will have an impact on our understanding of the lack of repair in diseases like multiple sclerosis. [unreadable] [unreadable]